+
Diabetes
Maureen McQueeney, PharmD, BCPS, BCACP, CDE
+
Learning Objectives

Describe each class of diabetic agents in detail including the
following: efficacy, indications, advantages, adverse effects,
contraindications and drug interactions.

Be familiar with how the oral and injectable agents compare in
terms of their effect on weight, the lipid profile, cost, HbA1c
reduction and fasting plasma reduction.

Demonstrate proper technique in preparing an insulin dose
including the specific sequence of steps in mixing insulins where
appropriate.

Describe medications that may cause hypo/hyperglycemia and
potential drug interactions
Pathophysiology of DM
Glucagon

BG
BG
Pathophysiology of DM
Little or no
insulin secreted
from pancreas
Insulin not
working at
tissue receptors
Glucagon

BG
 BG, but feedback is
that there is no glucose
to tissue
+ Pathophysiology of DM
5
Pancreas
Ingestion of
food
GI Tract
Release of gut
hormones
(Incretins:
GLP-1 and GIP)
 Insulin from β-cells
Glucose-dependent
Glucose
uptake by
adipose and
muscle
tissue
Blood glucose
homeostasis
b-cells
a-cells
DPP-IV
Glucose
production
by liver
 Glucagon
from α-cells
Glucose-dependent
In type 2 DM--- GLP-1and GIP
with loss of effect
Merck Medicus. Accessed April10, 2008. For educational purposes only.
+
Diabetes Medications
6
+
Patient Case #1
 HPI: H.G
is a 45 year old obese female who comes to
your clinic for a follow-up on her blood results and to
start a medication for her Type 2 DM. She refuses to
start insulin at this point.
 PMH: Type
2 diabetes (recently diagnosed)
Hypertension x 2 years, hyperlipidemia
 Medications: lisinopril
20 mg daily, hydrochlorothiazide
25 mg daily, aspirin 81 mg daily
7
+
Patient Case #1
 SH: Alcohol: (-), (-)
Smoking
 All: NKDA
 PE:
BP: 122/72, HR 77 Height: 5’5’’, Weight: 210 lbs, BMI:
35
 Labs: FPG: 210
mg/dL; PPG: 200 mg/dL; HbA1c: 8.0%;
Scr: 1.01; LFTs: WNLs
8
+
9
Patient Case #1
 Which
of the following medications is the most
appropriate initial medication for this patient?
Before we answer---lets talk about the
options!!!!
+
10
Biguanides1

Medications
Metformin (Glucophage ®)
 Metformin ER (Glucophage XR ®, Fortamet ER ®)


Mechanism of action
↓ hepatic glucose production
 ↑ insulin sensitivity


Effects
↓ A1c by 1.5%
 ↓ FPG

+
11
Biguanides1

Side effects




Contraindications/Precaution



Weight loss
Transient N/V/D
Lactic acidosis
Males w/SCr ≥ 1.5; females w/SCr ≥ 1.4
Caution in pts over 80 years of age
Additional comments



May have positive effect on lipid profile
ER formulation may be associated with less GI effects
May be taken with food to decrease GI effects
+
12
Sulfonylureas1
 Medications




Glipizide (Glucotrol ®)
Glipizide ER (Glucotrol XL ®)
Glyburide (Micronase ®, Diabeta ®)
Glimepride (Amaryl ®)
 Mechanism

of action
↑ pancreatic beta cell insulin secretion in a glucose independent
manner
+
13
Sulfonylureas1

Effects



Side effects



↓ A1c by 1.5%
↓ FPG and PPG (mixed effect)
Hypoglycemia
Weight gain
Additional comments



Glyburide should not be used in CrCl < 50 ml/min
Glipizide should be taken 30 minutes before meals
Other agents should be taken with meals
+
14
Short-Acting Secretagogues1

Medications



Mechanism of action


Repaglinide (Prandin ®)
Nateglinide (Starlix ®)
↑ pancreatic insulin secretion in a glucose-dependent
manner
Effects


↓ A1c by 0.6 – 1.5%
↓ PPG
+
15
Short-Acting Secretagogues1
 Side


effects
Weight gain
Hypoglycemia
 Additional



comments
Repaglinide more effective
Less hypoglycemia than sulfonylureas
Take before or with meals
 Repaglinide: immediately before or with meals
 Nateglinide:1-30 minutes prior to meals
+ Glucagon-Like Peptide 1
Agonists1,2
 Medication



Exenatide (Byetta ®)
Liraglutide (Victoza®)
Exenatide extended-release (Bydureon®)
 Mechanism




of action
↑ glucose-dependent insulin secretion
↓ glucagon secretion
↓ gastric emptying
↑ satiety
 Effects


↓ A1c by 0.5 – 1.0%
↓ PPG
16
+ Glucagon-Like Peptide 1

Side effects






Agonists1,2
N/V/D
Weight loss
Headache
Pancreatitis
Hypoglycemia
Additional comments



Subcutaneous injection
Use with sulfonylureas: ↓ sulfonylurea dose by 50% due to
risk of hypoglycemia
Take up to 60 minutes prior to morning and evening meals
17
+
18
Amylin Agonists1,3

Medication


Mechanism of action




Pramlintide (Symlin ®)
↓ gastric emptying
↓ glucagon production
↑ satiety
Effects


↓ A1c by 0.5 – 0.7%
↓ PPG
+
19
Amylin Agonists1,3

Side effects





Nausea
Anorexia
Weight loss
Hypoglycemia
Additional comments



Subcutaneous injection
Use with insulin: ↓ meal time insulin by 50% due to risk of
hypoglycemia
Used in type 1 and 2 DM
+ Dipeptidyl Peptidase 4 (DPP-4) Inhibitors4-6
 Medications
Sitagliptin (Januvia ®)
 Saxagliptin (Onglyza ®)
 Linagliptin (Tradjenta®)

 Mechanism

of action
↓ metabolism of incretin hormones
 Effects
↓ A1c by 0.62 – 0.85%
 ↓ PPG

20
+
21
DPP-4 Inhibitors4-6
 Side
effects
Nasopharyngitis
 URI
 Headache
 Abdominal pain
 N/D
 Hypersensitivity
 Pancreatitis (with sitagliptin)

 Additional

comments
Use with sulfonylureas: ↓ sulfonylurea dose by 50% due to
risk of hypoglycemia
+
22
DPP-4 Inhibitors4-6

Renal adjustment

Sitagliptin



CrCl< 50 ml/min: 50 mg daily
CrCl< 30 ml/min: 25 mg daily
Saxagliptin

CrCl< 50 ml/min: 2.5 mg daily
 Drug

Interactions
Saxagliptin is a CYP 3A4 substrate

Caution with strong 3A4 inhibitors
+
Back to Patient Case #1

HPI: HG is a 45 year old obese female who comes to
your clinic for a follow-up on her blood results and
start a medication for her Type 2 DM. She refuses to
start insulin at this point.

PMH: Type 2 diabetes (recently diagnosed)
Hypertension x 2 years, Hyperlipidemia

Medications: lisinopril 20 mg daily,
hydrochlorothiazide 25 mg daily, aspirin 81 mg daily
23
+
24
Back to Patient Case #1

SH: Alcohol: (-), (-) Smoking

All: NKDA

PE: BP: 122/72, HR: 77 Height: 5’5’’, Weight: 210 lbs,
BMI: 35

Labs: FPG: 210 mg/dL; PPG: 200 mg/dL; HbA1c: 8.0%;
Scr: 1.01; LFTs: WNLs
+
25
Back to Patient Case #1

Which of the following medications is the most
appropriate initial medication for this patient?

A. Glipizide

B. Sitagliptin

C. Pioglitazone

D. Metformin
+
26
Patient Case #2

RE is a 75 year old female who was referred to you by
her PCP for help with DM management. She was
recently diagnosed with Type 2 DM. She has a history of
CAD, hyperlipidemia, depression and HTN.

Her current medications include: aspirin 81mg daily,
Diovan 320 mg daily, Plavix 75 mg, ranitidine 150mg PO
BID, NTG PRN, metoprololsuccinate 50 mg daily, Crestor
40 mg daily, Cymbalta 90 mg daily
+
27
Patient Case #2
 Allergies/intolerances: ACEIs
 Vital
signs: BP: 123/61, HR: 62, wt: 135 lbs, ht: 5’5”,
 Labs: A1c
 Social

- cough
7.9%, Scr 1.43, LFTs: WNLs, CrCl: 31 ml/min
pearls
Patient has Medicare Part D and is very concerned about
reaching her the “donut hole”
+
28
Patient Case #2
 Which
of the following is most appropriate initial
treatment for this patients DM?
 A. Glyburide
2.5 mg PO BID
 B. Metformin
500 mg PO BID
 C. Saxagliptin
 D. Glipizide
5 mg daily
2.5 mg PO BID
+
Insulin Therapy
29
+
30
Insulin Therapy
 Medications
 Aspart
(Novolog ®)
 Lispro (Humalog ®)
 Glulisine (Apidra ®)
 Regular (Humulin R ®, Novolin R ®)
 NPH (Humulin N ®, Novolin N ®)
 Glargine (Lantus ®)
 Detemir (Levemir ®)
+
31
Insulin Therapy
 Medication

(continued)
Humalog Mix 75/25 ®
 75%
lispro protamine/25% lispro
 Humalog Mix 50/50 ®
 50% lispro protamine/50% lispro
 Novolog Mix 70/30 ®
 70% aspart protamine/30% aspart
 Humulin Mix 70/30 ® and Novolin Mix 70/30 ®
 70% NPH/30% regular
 Humulin Mix 50/50 ®
 50% NPH/50% regular
+
32
Insulin Therapy7
+
33
Insulin Therapy1

Mechanism of Action


Side effects



Exogenous administration of insulin
Hypoglycemia
Weight gain
Additional comments




Subcutaneous injection
Most effective treatment
Positive effect on HDL and TGs
Glargine and detemir cannot be mixed
+
34
Insulin Regimens8
 Nonphysiologic
Insulin regimen
+
35
Insulin Regimens8

Physiologic insulin regimen
+ Initiation of Insulin per ADA
Guidelines10
36
37
+

38
Insulin Titration11-12
Treat-to-Target algorithm
.
+

39
Sliding Scale Insulin13,14
Advantages




Disadvantages






Convenient and simple to initiate
Patient involvement in his/her therapy
Can be used to supplement scheduled insulin doses
Not supported by clinical literature
Treats hyperglycemia instead of preventing it
Lag time to onset of insulin
Poor glycemic control
Patient adherence and competency required
Not recommended in outpatient setting per ADA
+ Adjusting Insulin
Therapy15
40
Type
Injection Time
Affected BG reading
Rapid or Shortacting
Before Breakfast
Before Lunch
Before Lunch
Before Supper
Before Supper
Before Breakfast
2-3 hrs after supper
or bedtime
Before Supper
Before
Supper/Bedtime
Before Bedtime
Before Breakfast (next
morning)
Throughout the day
Intermediate-acting
or mixed insulin
Long-acting
+ Converting Between Types of
Types of Insulin
Insulin18-20
Recommendation
NPH to detemir
Convert unit-per-unit
Give detemir once daily or BID
NPH to glargine
NPH once daily: unit-per-unit give
once daily
NPH twice daily: added total NPH
dose and reduce by 20% give
once daily
Detemir or glargine to Convert unit-per-unit
NPH
Give NPH at bedtime or BID
Detemir to glargine or Concert unit-per-unit
glargine to detemir
Give once daily or BID if
necessary
41
+ Converting Between Types of
Insulin Regimens21
 Regular

to Rapid
Total up daily dose then split between meals
 One
basal injection → Add rapid-acting insulin at
largest meal



Give 10% of total daily dose as rapid-acting analog at largest
meal
Reduce basal dose by 10%
Can give additional insulin injections before all meals if
necessary
42
+ Converting Between Types of
Insulin Regimens21
 One

Divide total daily dose in half



Give pre-breakfast and pre-supper premix insulin
The largest meal requires a larger proportion of insulin
Reduce total dose by 20% if recurrent hypoglycemia
 One

premix injection → 2 premix injections
Divide TDD in half


basal injection → Two premix injections
Give before breakfast and dinner
Reduce total dose by 20% if recurrent hypoglycemia
43
+
44
Conversion Example

Convert to physiologic regimen using Lantus and Humalog
insulin
Insulin
AM
PM
NPH
8
12
Regular
6
10
+
45
Conversion Example


What should the total Lantus® dose be?

A. 20 units

B. 18 units

C. 16 units

D. 14 units
What should the Humalog® dose be?

A. 5 units before breakfast, lunch and dinner

B. 5 units before breakfast and lunch and 6 units before dinner

C. 8 units before breakfast and dinner

D. 6 units before breakfast and 10 units before dinner
+
Treatment Strategies
46
+ Contributions of FPG and PPG to
Overall A1C22
Fasting
PostPrandial
Diabetes Care. 2003;26:881-885. 47
+
+
AACE Treatment Guidelines23

Monotherapy: HbA1c 6-7%



Options: metformin, TZDs, secretagogues, DPP-4 inhibitors, alphaglucosidase inhibitors
Monitor and titrate every 2-3 months
Consider combination therapy if goals not met after 2-3 months

Combination therapy: HbA1c 6-7%

Initiation/intensify combination therapy: A1c 8-10%

Initiate/intensify insulin: A1c > 10%

Consider basal-bolus insulin therapy: A1c > 8.5%
49
+ Patient Case #3

HPI: AT is a 64 year old female with a history of
Type 2 DM. She is reporting to clinic for evaluation
of DM control.

PMH: Type 2 DM since 2005, hyperlipidemia,
depression and GERD

Medications: metformin 1000 mg PO BID,
glyburide 10mg PO BID, omeprazole 20 mg daily,
Lipitor 20 mg daily
50
+ Patient Case #3

Allergies: NKDA

SH: (+) smoking: 1 ppd, occ ETOH

Vital signs: BP: 149/58, HR: 60, Height: 63.5 in,
Weight: 138 lbs

BG per glucometer: FBG: 80s-110s, PPG: 200-220s
51
+
Patient Case #3

Labs: A1c: 7.3%
LFTs: WNLs
Scr: 0.71
Total cholesterol: 138
Triglycerides 121 HDL: 31
LDL: 83

Social pearls

Patient refuses to start insulin therapy at this point despite
extensive education regarding the benefits of insulin
therapy. She is fearful of the injection and potential for
weight gain.
52
+
Patient Case #3

Which of the following treatment recommendations would
be the most appropriate for this patient?

A. Sitagliptin 100 mg daily

B. Byetta 10 mcg SC before breakfast and dinner

C. Nateglinide 60mg PO TID

D. Pioglitazone 30 mg PO daily
53
+
Patient Case #4

GR is a 57 year obese male with a PMH history of
Type 2 DM, hyperlipidemia and HTN who reports
to the clinic for a follow up on his DM management
and to discuss weight loss options.

Medications: metformin 850 mg PO TID,
simvastatin 80 mg QHS, lisinopril 80 mg daily,
diltiazem ER 360 mg daily, nefazodone 300mg PO
BID

Allergies: NKDA
54
+
Patient Case #4

Vital signs: BP: 145/82, HR: 82, Weight: 300 lbs, Height 6’0”,
BMI: 40.8

Labs: A1c 7.3%, Scr: 1.10; LFTs: WNLs

BG per glucometer
Date
Before Breakfast
2-hr post prandial
9/17/2012
81
220
9/16/2012
110
210
9/15/2012
99
195
9/14/2012
112
213
9/13/2012
120
222
9/12/2012
92
187
55
+
Patient Case #4

Which of the following is most appropriate
recommendation for management of GRs DM?
 A. Byetta
5 mcg SC BID
 B. Saxagliptin
 C. Humalog
 D. Lantus
5 mg PO daily
4 units before largest meal
10 units QHS
56
+
Patient Case #5

EM is a 54 year old male who was recently started
on Lantus insulin. You were asked to make a
recommendation regarding his diabetes regimen.
He is currently taking metformin 1000mg PO BID,
glyburide 10 mg PO BID and Lantus 38 units at
bedtime (increased from 30 units last week),
simvastatin 80mg QHS and lisinopril 20 mg daily
57
+
Patient Case #5

BG per patient glucometer
Date
Before Breakfast
9/17/2012
267
9/16/2012
227
9/15/2012
215
9/14/2012
Bedtime
248
302
9/13/2012
274
9/12/2012
168
58
+
Patient Case #5

SH: (+) smoking: 1 ppd, occ ETOH

Vital signs: BP: 130/58, HR: 60, Height: 67 in, Weight: 255 lbs

Fasting Lipid panel
Total Cholesterol: 148
HDL: 30

Triglycerides: 289
LDL: 65
Labs: A1c: 9.5%; Scr 1.13 mg/dL
59
+
Patient Case #5

What is the most appropriate recommendation for this
patients DM treatment?

A. Increase Lantus insulin to 40 units

B. Add Humalog 4 units before his biggest meal

C. Increase Lantus insulin to 46 units

D. Increase Lantus insulin to 44 units and add Humalog 4
units before breakfast and dinner
60
+
Patient Case # 6

EM comes back to the clinic after several visits and his
current diabetes regimen includes: metformin 1000mg
PO BID, Lantus insulin 60 units QHS.

Most recent labs



A1c: 7.3%
SCr: 1.13 mg/dL
FPG 80-110s
61
+
Patient Case #6

What would be the most appropriate recommendation at this time?
A) Increase Lantus to 65 units
B) Add Januvia 100 mg daily
C) Advise patient to test BS before meals and at bedtime
D) Add 10 units of Regular insulin before breakfast
62
+

Patient Case #6
EM takes your advice and checks his BG before meals and at
bedtime for the last week.
Date
Before Breakfast
Before Lunch
Before Dinner
Bedtime
Mon
80
131
156
241
Tues
111
141
161
189
Wed
96
121
167
170
Thurs
85
100
171
193
Fri
100
189
200
171
Sat
112
145
167
211
Sun
99
110
131
199
63
+
Patient Case #6

What would be the most appropriate
recommendation for EM at this time?
 Add
Humalog 4 units before breakfast
 Add
Apidra 4 units before lunch
 Add
Novolog 4 units before dinner
64
+
Insulin Administration
+
ADMINISTRATION OF INSULIN

Preparation of insulin using vial and syringe:




Hands and injection should be cleaned
Remove the cap on the insulin vial and sterilize the top with an
alcohol swab

If using NPH or mixed insulin roll gently between hands

Do not shake vigorously
Draw air into the syringe that is equal to the amount of insulin to
be injected and push that air into the vial
Draw up amount of insulin to be given

Air bubbles not dangerous

Can cause less dose to be injected
+
ADMINISTRATION OF INSULIN

Preparation of insulin by insulin pen device




Hands and injection site should be cleaned
Wipe the rubber seal on the pen body with an alcohol
swab
 If using NPH or mixed insulin roll the pen gently
between hands
 Do not shake
Prime the pen by dialing to 2 units of insulin (do this with
every use)
Select the required dose by turning the dial until it
reached the desired dose
+
ADMINISTRATION OF INSULIN

Subcutaneous technique






Lightly grasp a fold of skin (“pinch an inch”)
Inject at a 90° angle
Release the skin fold
Push the plunger down
Wait at least 5 seconds after complete depression of plunger
If painful, blood or clear fluid is seen after withdrawing the
needle, apply pressure for 5-10 seconds without rubbing
+ADMINISTRATION OF INSULIN

Rate of absorption: abdomen > arms > thighs > buttocks area
+
MIXING OF INSULIN
Column 1_____________________
_Column 2
Humalog
NPH
Novolog
Glargine
Regular
Apidra
Detemir
+
QUESTIONS?
71
+
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in
type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.
Diabetes Care 2008;31:1-11.
Byetta [package insert]. San Diego (NC): Amylin Pharmaceuticals, Inc and Eli Lilly
and Company; 2007.
Symlin [package insert]. San Diego (NC): Amylin Pharmaceuticals, Inc; 2005.
Covey DF, Rodgers PT. New therapeutics options for improving glycemic control in
patients with type 2 diabetes mellitus.
Januvia [package insert]. Whitehouse Station (NJ): MERCK & CO., INC.;2008
Onglyza [package insert]. Princeton (NJ): Bristol-Myers Squibb; 2009
Lexi-Comp Online™, Hudson, Ohio: Lexi-Comp, Inc.; 2008; November 2, 2008.
DeWitt DE, Dugdale DC. Using new insulin strategies in the outpatient treatment of
diabetes. JAMA 2003;289(17):2254-2264.
Dipiro JT, Wells BG, Schwinghammer TL, Hamilton CW. Pharmacotherapy handbook.
6th ed. New York: McGraw-Hill, 2006.
Nathan DM, Buse JB, Davidson MB, et al. Medical management of
hyperglycemia
in type 2 diabetes: a consensus algorithm for the initiation and adjustment of
therapy. Diabetes Care 2008;31(12):1–11. Nathan DM, Buse JB, Davidson MB, et al.
Medical management of hyperglycemia in type 2 diabetes: a consensus
algorithm for the initiation and adjustment of therapy. Diabetes Care 2008;31(12):1–
11.
72
+ References
11.
12.
13.
14.
15.
16.
17.
18.
19
20.
21.
Riddle MC, Rosenstock J, and Gerich J. The Treat-to-target trial: randomized addition of
glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care
2003;26(11):3080-3086.
Unger Jeff. Management of Type 1 Diabetes. Prim Care Clin Office Pract. 2007; 34: 791808.
Umpierrez GE, Palacio A, Smiley D. Sliding scale insulin use: myth or insanity? The
American Journal of Medicine 2007; 120: 563-567.
Hirsch IB, Farkas-Hirsch R. Sliding scale or sliding scare: it’s all sliding nonsense. Diabetes
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